Pericyte MyD88 and IRAK4 control inflammatory and fibrotic responses to tissue injury
Open accessAbstract
Fibrotic disease is associated with matrix deposition that results in the loss of organ function. Pericytes, the precursors of myofibroblasts, are a source of pathological matrix collagens and may be promising targets for treating fibrogenesis. Here, we have shown that pericytes activate a TLR2/4- and MyD88-dependent proinflammatory program in response to tissue injury. Similarly to classic immune cells, pericytes activate the NLRP3 inflammasome, leading to IL-1β and IL-18 secretion. Released IL-1β signals through pericyte MyD88 to amplify this response. Unexpectedly, we found that MyD88 and its downstream effector kinase IRAK4 intrinsically control pericyte migration and conversion to myofibroblasts. Specific ablation of MyD88 in pericytes or pharmacological inhibition of MyD88 signaling by an IRAK4 inhibitor in vivo protected against kidney injury by profoundly attenuating tissue injury, activation, and differentiation of myofibroblasts. Our data show that in pericytes, MyD88 and IRAK4 are key regulators of 2 major injury responses: inflammatory and fibrogenic. Moreover, these findings suggest that disruption of this MyD88-dependent pathway in pericytes might be a potential therapeutic approach to inhibit fibrogenesis and promote regeneration.
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Emerging technologies can measure multiple omic readouts (genomes, epigenomes, transcriptomes, proteomes) in single cells.
“emerging technologies are now able to measure multiple “omic” readouts (genomes, epigenomes, transcriptomes and proteomes) in single cells174–176”
From Fibrosis: from mechanisms to medicines (2020) · cites this paper as [174]
Single-cell genomics methodologies have already yielded multiple new discoveries in fibrotic disease.
“Single-cell genomics methodologies have already yielded multiple new discoveries in fibrotic disease that would previously have been unattainable.”
From Fibrosis: from mechanisms to medicines (2020) · cites this paper as [174]
Combining molecular imaging of fibrosis with single-cell genomics could improve patient diagnostics, staging, prognostication, stratification, and cohort enrichment, optimizing clinical trial design.
“combining molecular imaging of fibrosis185 with cutting edge omic approaches such as single cell genomics174–176 could markedly improve patient diagnostics, staging, prognostication, stratification and cohort enrichment, which would in turn optimize clinical trial design”
From Fibrosis: from mechanisms to medicines (2020) · cites this paper as [174]
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References 59 · Cited by 151
Research works printed but not linked: 1
- Winkler EA, Sagare AP, Zlokovic BV. The peri- cyte: a forgotten cell type with important impli- cations for Alzheimer's disease? Brain Pathol. 2014;24(4):371-386.
- Authors
- Leaf, I. A., Nakagawa, S., Johnson, B. G., Cha, J. J., Mittelsteadt, K., Guckian, K. M., Gomez, I. G., Altemeier, W. A., & Duffield, J. S.
- Affiliations
- Center for Infectious Disease Research (US)
- University of Washington (US)
- Biogen (United States) (US)
- Corresponding author
- Leaf, Irina A.
- Duffield, Jeremy S.
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2016-11-21
- Volume
- 127
- Issue
- 1
- Pages
- 321-334
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC5199713
- OpenAlex
- W2552360097
- Cited by
- 151
- References
- 59
- Citations by year
- 2026: 9 · 2025: 13 · 2024: 15 · 2023: 13 · 2022: 10 · 2021: 21 · 2020: 16 · 2019: 20 · 2018: 19 · 2017: 12 · 2016: 2 · 2015: 1
- FWCI
- 10.69
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Heart Association (12040023)
- Biogen (DK094768, DK093493)
- University of Washington
- National Institutes of Health (UH2TR000504, UH3TR000504, TR000504)
- Japan Society for the Promotion of Science (16K18939)
- National Heart, Lung, and Blood Institute (R01HL122895)
- National Institute of Diabetes and Digestive and Kidney Diseases (RC1DK087389, R24DK094768, R01DK093493)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Health Sciences › Medicine › Nephrology › Acute Kidney Injury Research
- Keywords
- pericytes, MyD88, IRAK4, TLR2/4 signaling, NLRP3 inflammasome, IL-1β, IL-18, myofibroblast differentiation, pericyte migration, tissue damage, renal fibrosis, fibrogenesis, inflammation, TLR4
- MeSH terms
- Animals, Cells, Cultured, Fibrosis, Humans, Signal Transduction, Mice, Knockout, Pericytes, Mice, Interleukin-1beta, Interleukin-1 Receptor-Associated Kinases, Myeloid Differentiation Factor 88, Acute Kidney Injury, Myofibroblasts
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